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Super-enhancer–driven EFNA1 fuels tumor progression in cervical cancer via the FOSL2-Src/AKT/STAT3 axis
Shu-Qiang Liu, … , Chun-Ling Luo, Jin-Xin Bei
Shu-Qiang Liu, … , Chun-Ling Luo, Jin-Xin Bei
Published February 18, 2025
Citation Information: J Clin Invest. 2025;135(8):e177599. https://doi.org/10.1172/JCI177599.
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Research Article Cell biology Oncology Article has an altmetric score of 2

Super-enhancer–driven EFNA1 fuels tumor progression in cervical cancer via the FOSL2-Src/AKT/STAT3 axis

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Abstract

Super-enhancers (SEs) are expansive cis-regulatory elements known for amplifying oncogene expression across various cancers. However, their role in cervical cancer (CC), a remarkable global malignancy affecting women, remains underexplored. Here we applied integrated epigenomic and transcriptomic profiling to delineate the distinct SE landscape in CC by analyzing paired tumor and normal tissues. Our study identifies a tumor-specific SE at the EFNA1 locus that drives EFNA1 expression in CC. Mechanically, the EFNA1-SE region contains consensus sequences for the transcription factor FOSL2, whose knockdown markedly suppressed luciferase activity and diminished H3K27ac enrichment within the SE region. Functional analyses further underlined EFNA1’s oncogenic role in CC, linking its overexpression to poor patient outcomes. EFNA1 knockdown strikingly reduced CC cell proliferation, migration, and tumor growth. Moreover, EFNA1 cis-interacted with its receptor EphA2, leading to decreased EphA2 tyrosine phosphorylation and subsequent activation of the Src/AKT/STAT3 forward signaling pathway. Inhibition of this pathway with specific inhibitors substantially attenuated the tumorigenic capacity of EFNA1-overexpressing CC cells in both in vitro and in vivo models. Collectively, our study unveils the critical role of SEs in promoting tumor progression through the FOSL2-EFNA1-EphA2-Src/AKT/STAT3 axis, providing new prognostic and therapeutic avenues for CC patients.

Authors

Shu-Qiang Liu, Xi-Xi Cheng, Shuai He, Tao Xia, Yi-Qi Li, Wan Peng, Ya-Qing Zhou, Zi-Hao Xu, Mi-Si He, Yang Liu, Pan-Pan Wei, Song-Hua Yuan, Chang Liu, Shu-Lan Sun, Dong-Ling Zou, Min Zheng, Chun-Yan Lan, Chun-Ling Luo, Jin-Xin Bei

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Figure 1

Global landscape of SEs in CC.

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Global landscape of SEs in CC.
(A) Graphical overview of the study desig...
(A) Graphical overview of the study design. (B) Principal component analysis (PCA) of H3K27ac levels from 2,614 SEs in 9 CC samples and their corresponding normal tissues. Tumor (red) and normal samples (blue) are represented by circles. (C) Heatmap illustrating differential SE activity in the 9 CC samples compared with their paired normal tissues. H3K27ac signals are raw-scaled, with the color spectrum ranging from red (high intensity) to blue (low intensity), indicating H3K27ac signal intensity. (D) Visualization of H3K27ac signals across 2,614 SEs. The x axis represents individual SEs, while the y axis portrays the log2 fold change in H3K27ac signals in CC relative to matched normal tissues. Red dots highlight 26 genes upregulated in CC compared with normal tissues that are considered potential SE targets. Numbers in parentheses indicate the rank order based on the fold increase of SEs in CC relative to normal counterparts. (E) Venn diagram illustrating the overlap between genes with upregulated expression in tumor and those targeted by elevated SEs in CC. (F) Scatterplot showing survival analysis for the 26 SE-targeted genes identified in E. The x axis represents hazard ratio (HR), and the y axis represents P values. Horizontal dashed line represents P = 0.05, and vertical dashed line represents HR = 1. Genes marked in red are upregulated and have a significant association with a poorer overall survival rate in CC patients. Patients were divided into 2 groups based on the median expression level of each gene. The statistical significance of differences between the 2 groups was assessed using the log-rank test. (G) H3K27ac ChIP-Seq signals mapped proximate to the EFNA1 locus in CC (T) and NOR samples (N).

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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